The KIR (Killer-cell Immunoglobulin-like Receptor) gene family comprises six activating genes, others being inhibitory ones. Due to the existence of different KIR haplotypes, humans differ from one another in the number of inherited activating KIR genes. They may inherit zero to a full complement of six of these genes. The KIR gene variations have been shown to affect human’s susceptibility to a wide variety of human diseases. In this study, we sought to determine whether variations in the numbers of activating KIR gene in humans bear any associations with Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract in which genetic factors have been shown to play an important role. We used the candidate gene approach, whereby we genotyped cases and controls for all six activating KIR genes by PCR using gene-specific primers in three independent cohorts (Montreal, Ottawa and Winnipeg) of Canadian Caucasian CD patients and determined associations using unconditional logistic regression. We observed strong associations between most of the genes and CD in all the three cohorts of the patients. An overall analysis for all the cohorts showed strong associations with four of the genes. We also investigated the expression of KIR and non-KIR receptors and different integrins on peripheral blood NK cells in Crohn disease (CD) patients vis-a-vis healthy control subjects. Furthermore, we also determined recent degranulation history and cytotoxic potential of NK cells using freshly isolated peripheral blood from both CD patients and healthy control subjects. Our results show that NK cells from CD patients expressed higher levels of activating KIR as well as other non-KIR activating receptors. They also showed increased frequencies of the cells expressing these receptors. NK cells from the patients also expressed increased levels of different gut-homing integrin molecules. Furthermore, NK cells from CD patients showed a recent history of increased cytotoxic events and exhibited higher cytotoxicity. Collectively, this study shows that activating KIR genes confer risk for CD in both children and adults and peripheral blood NK cells in CD patients are more activated and more cytotoxic compared with their counterparts from healthy individuals. Our results provide novel insights on the immuno-pathogenesis of the disease and bear implications for devising novel immunotherapies.